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T U M O U R I M M U N O L O G Y

Keeping virus-driven lymphomas in check EpsteinBarr virus (EBV) is rapidly cleared by the immune system,but it can persist in some cells for life. Under conditions of immunosuppression, B cells that are latently infected with EBVcan undergo marked proliferation and malignant transformation.EBV latent membrane protein 1 (LMP1) is essential for thetransformation of human B cells. Here, the authors generated amouse model in which all B cells expressed LMP1. LMP1 + B cellswere efficiently deleted by T cells in immunocompetent animals,but they underwent marked clonal expansion and formed largeB cell lymphomas in immunocompromised animals. Both CD4 + and CD8 + T cells contributed to immune surveillance of LMP1 + B cells. Natural killer (NK) cells were also activated by LMP1 + B cells,which expressed ligands for the NK cell receptor NKG2D. Indeed,treatment of tumour-bearing mice with an NKG2DFc fusionprotein caused efficient lysis of LMP1 + tumour cells, suggestinga possible new therapy for EBV-driven B cell lymphomas.ORIGINAL RESEARCH PAPER Zhang, B. et al. Immune surveillance and therapy of lymphomasdriven by Epstein-Barr virus protein LMP1 in a mouse model. Cell 148 , 739751 (2012)

I M M U N O T H E R A P Y

A killer combinationIn this study, a combination of the tumour-targeting antibodytrastuzumab (which is specific for human epidermal growth factorreceptor 2 (HER2)) and a natural killer (NK) cell-activating antibodyspecific for CD137 is shown to be highly effective in treating breastcancer. Trastuzumab leads to the elimination of HER2 + breastcancer cells mainly through antibody-dependent cell-mediatedcytotoxicity by NK cells. NK cells exposed to trastuzumab-coatedHER2+ tumour cells upregulate the co-stimulatory moleculeCD137, and subsequent treatment with a CD137-specific agonisticantibody improved their ability to kill trastuzumab-coated HER2 + tumour cells in vitro . Moreover, athymic mice (which lack T cellsbut have normal NK cells) that were engrafted with human

breast cancer cells and treated with trastuzumab followed bythe CD137-specific antibody showed a marked reduction intumour size and mortality compared with mice treated withonly one antibody. The enhanced cytotoxicity was restricted toantibody-coated tumour cells, which suggests that this combinedtherapy could be applicable to other cancer-targeting antibodies.ORIGINAL RESEARCH PAPER Kohrt, H. E. et al. Stimulation of natural killer cells with aCD137-specific antibody enhances trastuzumab efficacy in xenotransplant models of breast cancer. J. Clin. Invest. 122 , 10661075 (2012)

T U M O U R I M M U N O L O G Y

Hope in a sticky situationDuring tumorigenesis, the hypoxic tumour environment promotesthe formation of new blood vessels that show many abnormalitiescompared with healthy vasculature. Leukocyte adhesion toendothelial cells lining the tumour-associated vasculature isimpaired and, consequently, effector immune cells cannotgain access to the tumour. In this study, the authors treatedtumour-bearing mice with a tumour necrosis factor (TNF)peptidefusion protein that targets TNF to the tumour-associatedvasculature. They found that this therapy promoted theupregulation of adhesion molecules on endothelial cells andincreased the infiltration of CD8 + T cells into tumours. In micewith ovalbumin-expressing tumours, delivery of the fusion proteinmarkedly increased the antitumour responses of adoptivelytransferred ovalbumin-specific CD8 + T cells. The authors suggestthat a similar approach could be used to improve the efficacy of adoptive T cell transfer-based therapies for cancer.ORIGINAL RESEARCH PAPER Calcinotto, A. et al. Targeting TNF- to neoangiogenicvessels enhances lymphocyte infiltration in tumors and increases the therapeutic potentialof immunotherapy. J. Immunol. 188 , 26872694 (2012)

IN BRIEF

R E S E A R C H H I G H L I G H T S

NATURE REVIEWS | IMMUNOLOGY VOLUME 12 | JANUARY 2012

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